Crystal form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3) pyridazine-3-carboxamide

ABSTRACT

Disclosed is crystalline Form A of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) amino)-N-(methyl-d3)pyridazine-3-carboxamide. Form A is a neat crystalline form. Characterization data for Form A are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/478,789, filed Mar. 30, 2017, the disclosure of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to a crystalline form of6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide.

BACKGROUND OF THE INVENTION

The compound,6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide,has the structure of Formula (0:

and is referred to herein as “Compound (I)”. Compound (I) is disclosedas Example 52 in U.S. Pat. No. 9,505,748 B2, which is assigned to thepresent assignee. U.S. Pat. No. 9,505,748 B2 also discloses methods oftreatment employing Compound (I).

Compound (I) is a Tyk2 inhibitor currently in clinical trials for thetreatment of auto-immune and auto-inflammatory diseases such aspsoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjögren'ssyndrome, inflammatory bowel disease, Crohn's disease and ankylosingspondylitis.

In the synthesis of a chemical compound intended for pharmaceutical use,it is necessary to isolate and purify the compound at the completion ofthe synthetic process and prior to further processing to provide thecompound in a pharmaceutical formulation. The isolation and thepurification steps, which can be combined or separate consecutive steps,provide the compound as a purified solid with minimal loss of yieldduring isolation from other components of the reaction mixture and/orduring purification to remove impurities from the isolated compoundsample.

It is desirable to provide a solid form that can be reproduciblyproduced from the isolation and/or purification steps.

Further, it is desirable to isolate the purified compound in a solidform that is physically and chemically stable at a range of storageconditions, such as at different conditions of temperature and humidity.

Furthermore, it is also desired to provide the compound in a solid formthat is amenable to additional processing, for example, in which it canbe converted into other solids forms, such as an amorphous form.

Still furthermore, it is desired to provide a compound in a solid formthat has sufficient solubility in solvents/solutions to permitpreparation of other solid forms.

The Applicants have found a crystalline form of Compound (I) thatsurprisingly provides Compound (I) in a solid form that is physicallyand chemically stable at a range of storage conditions.

Further, the Applicants have found a crystalline form of Compound (I)that surprisingly provides Compound (I) in a solid form that isphysically and chemically stable at a range of storage conditions and isamenable to additional processing, for example, in which it can beconverted into other solids forms, such as an amorphous form.

Further, the Applicants have found a crystalline form of Compound (I)that surprisingly provides Compound (I) in a solid form that isphysically and chemically stable at a range of storage conditions, isamenable to additional processing, for example, in which it can beconverted into other solids forms, such as an amorphous form, and hassufficient solubility in solvents/solutions to permit preparation ofother solid forms.

The present invention is also directed to other important aspects.

SUMMARY OF THE INVENTION

The present invention provides crystalline Form A of Compound (I). Thename used herein to characterize a specific form, e.g. “Form A” etc.,should not be considered limiting with respect to any other substancepossessing similar or identical physical and chemical characteristics,but rather it should be understood that this designation is a mereidentifier that should be interpreted according to the characterizationinformation also presented herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. shows the observed powder x-ray diffraction pattern (CuKα,λ=1.54178 Å at T=25° C.) of crystalline Form A of Compound (I).

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram ofcrystalline Form A of Compound (I).

FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of the Form Aof Compound (I).

FIG. 4 shows a moisture-sorption isotherm for Form A of Compound (I)measured at 25° C.

DETAILED DESCRIPTION OF THE INVENTION

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof.

The names used herein to characterize a specific form, e.g., “Form A”etc., are merely identifiers that are to be interpreted in accordancewith the characterization information presented herein and are not to belimited so as to exclude any other substance possessing similar oridentical physical and chemical characteristics.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

All numbers expressing quantities of ingredients, weight percentages,temperatures, and so forth that are preceded by the word “about” are tobe understood as only approximations so that slight variations above andbelow the stated number may be used to achieve substantially the sameresults as the stated number. Accordingly, unless indicated to thecontrary, numerical parameters preceded by the word “about” areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

All measurements are subject to experimental error and are within thespirit of the invention.

As used herein, “polymorphs” refer to crystalline forms having the samechemical structure but different spatial arrangements of the moleculesand/or ions forming the crystals.

As used herein, “amorphous” refers to a solid form of a molecule and/orion that is not crystalline. An amorphous solid does not display adefinitive X-ray diffraction pattern with sharp maxima.

As used herein, “substantially pure,” when used in reference to acrystalline form, means a compound having a purity greater than 90weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and99 weight %, and also including equal to about 100 weight % of Compound(I), based on the weight of the compound. The remaining materialcomprises other form(s) of the compound, and/or reaction impuritiesand/or processing impurities arising from its preparation. For example,a crystalline form of Compound (I) may be deemed substantially pure inthat it has a purity greater than 90 weight %, as measured by means thatare at this time known and generally accepted in the art, where theremaining less than 10 weight % of material comprises amorphous and/orother form(s) of Compound (I) and/or reaction impurities and/orprocessing impurities.

As used herein, a powder x-ray diffraction (PXRD) pattern “comprising” anumber of peaks selected from a specified group of peaks, is intended toinclude PXRD patterns having additional peaks that are not included inthe specified group of peaks. For example, a PXRD pattern comprisingfour or more, preferably five or more, 20 values selected from: A, B, C,D, E, F, G, and H, is intended to include a PXRD pattern having: (a)four or more, preferably five or more, 20 values selected from: A, B, C,D, E, F, G, and H; and (b) zero or more peaks that are not one of peaksA, B, C, D, E, F, G, and H.

The presence of reaction impurities and/or processing impurities may bedetermined by analytical techniques known in the art, such as, forexample, chromatography, nuclear magnetic resonance spectroscopy, massspectrometry, and/or infrared spectroscopy.

As used herein, the unit cell parameter “molecules per unit cell” refersto the number of molecules of Compound (I) in the unit cell.

Form A of Example (I)

In one embodiment, Compound (I) is provided as a crystalline materialcomprising Form A. The crystalline Form A of Compound (I) is a neatcrystalline form.

In one embodiment, crystalline Form A of Compound (I) is characterizedby unit cell parameters approximately equal to the following:

a=8.90±0.05 Å

b=10.48±0.05 Å

c=11.34±0.05 Å

α=96.7±0.5°

β=90.8±0.5°

γ=100.4±0.5°

Space group: P-1

Molecules per unit cell (Z): 2

Unit cell volume=1032±10 Å³

Calculated density 1.369 g/cm³

wherein the unit cell parameters of Form A of Compound (I) are measuredat a temperature of about 25° C.

TABLE 1 Form A of Compound (I) Selected PXRD 2θ values (CuKα λ = 1.5418Å) 7.8 ± 8.6 ± 10.1 ± 10.9 ± 12.0 ± 12.3 ± 12.6 ± 0.2 0.2 0.2 0.2 0.20.2 0.2 13.0 ± 14.0 ± 14.4 ± 14.7 ± 15.8 ± 17.3 ± 18.3 ± 0.2 0.2 0.2 0.20.2 0.2 0.2 18.8 ± 19.3 ± 19.8 ± 20.4 ± 21.5 ± 22.0 ± 23.1 ± 0.2 0.2 0.20.2 0.2 0.2 0.2 23.7 ± 24.2 ± 25.3 ± 26.2 ± 27.2 ± 28.2 ± 29.1 ± 0.2 0.20.2 0.2 0.2 0.2 0.2 29.7 ± 30.2 ± 30.8 ± 31.4 ± — — — 0.2 0.2 0.2 0.2

In one embodiment, crystalline Form A of Compound (I) is characterizedby a powder x-ray diffraction pattern comprising four or more 20 values(CuKα λ=1.5418 Å) selected from: 7.8±0.2; 8.7±0.2; 10.1±0.2; 12.0±0.2;12.4±0.2; 13.0±0.2; 15.8±0.2; 18.9±0.2; 19.3±0.2; and 20.4±0.2, whereinthe PXRD pattern of Form A is measured at a temperature of about 25° C.;

In one embodiment, crystalline Form A of Compound (I) is characterizedby a powder x-ray diffraction pattern comprising five or more 20 values(CuKα λ=1.5418 Å) selected from: 7.8±0.2; 8.7±0.2; 10.1±0.2; 12.0±0.2;12.4±0.2; 13.0±0.2; 15.8±0.2; 18.9±0.2; 19.3±0.2; and 20.4±0.2, whereinthe PXRD pattern of Form A is measured at a temperature of about 25° C.;

In one embodiment, crystalline Form A of Compound (I) is characterizedby a powder x-ray diffraction pattern comprising six or more 20 values(CuKα λ=1.5418 Å) selected from: 7.8±0.2; 8.7±0.2; 10.1±0.2; 12.0±0.2;12.4±0.2; 13.0±0.2; 15.8±0.2; 18.9±0.2; 19.3±0.2; and 20.4±0.2, whereinthe PXRD pattern of Form A is measured at a temperature of about 25° C.;

In one embodiment, crystalline Form A of Compound (I) is characterizedby a powder x-ray diffraction pattern comprising 20 values (CuKαX=1.5418 Å) at 10.1±0.2 and 15.8±0.2; and three or more 20 values (CuKαX=1.5418 Å) selected from: 7.8±0.2; 8.7±0.2; 12.0±0.2; 12.4±0.2;13.0±0.2; 15.8±0.2; 18.9±0.2; and 19.3±0.2, wherein the PXRD pattern ofForm A is measured at a temperature of about 25° C.

In one embodiment, crystalline Form A of Compound (I) is characterizedby (i) a powder x-ray diffraction pattern comprising the 20 values (CuKαX=1.5418 Å) at 10.1±0.2 and 15.8±0.2; measured at a temperature of about25° C.; and (ii) an endotherm in the range of from 264° C. to 269° C.

In one embodiment, crystalline Form A of Compound (I) is characterizedby an observed powder x-ray diffraction pattern substantially as shownin FIG. 1.

In one embodiment, crystalline Form A of Compound (I) is characterizedby an endotherm in the range of from 264° C. to 269° C.

In one embodiment, crystalline Form A of Compound (I) is characterizedby a differential scanning calorimetry (DSC) thermogram substantially asshown in FIG. 2.

In one embodiment, crystalline Form A of Compound (I) is characterizedby (i) a powder x-ray diffraction pattern comprising the 2θ values (CuKαX=1.5418 Å) at 10.1±0.2 and 15.8±0.2, measured at a temperature of about25° C.; and (ii) a differential scanning calorimetry (DSC) thermogramsubstantially in accordance with that shown in FIG. 2.

In one embodiment, crystalline Form A of Compound (I) is characterizedby a thermogravimetric analysis (TGA) thermogram having weight loss ofless than 0.2%, based on the weight of the sample of Form A, upon beingheated to a temperature of about 150° C.

In one embodiment, crystalline Form A of Compound (I) exhibits athermogravimetric analysis (TGA) thermogram substantially as shown inFIG. 3.

In one embodiment, crystalline Form A of Compound (I) exhibits amoisture-sorption isotherm substantially as shown in FIG. 4.

In still yet an even further embodiment, crystalline Form A of Compound(I) is substantially pure.

In another embodiment, the crystalline form of Compound (I) consistsessentially of Form A. The crystalline form of this embodiment maycomprise at least about 90 wt. %, preferably at least about 95 wt. %,and more preferably at least about 99 wt. %, based on the weight of thecrystalline form, Form A of Compound (I).

One embodiment provides a composition comprising6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide, wherein at least 95 wt. %,preferably at least 97 wt. %, and more preferably at least 99 wt. % ofsaid6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide is in crystalline Form A.

Crystalline forms may be prepared by a variety of methods, including forexample, crystallization or recrystallization from a suitable solvent,sublimation, growth from a melt, solid state transformation from anotherphase, crystallization from a supercritical fluid, and jet spraying.Techniques for crystallization or recrystallization of crystalline formsfrom a solvent mixture include, for example, evaporation of the solvent,decreasing the temperature of the solvent mixture, crystal seeding asupersaturated solvent mixture of the molecule and/or salt, freezedrying the solvent mixture, and addition of antisolvents(countersolvents) to the solvent mixture. High throughputcrystallization techniques may be employed to prepare crystalline formsincluding polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals are discussed in Solid-State Chemistryof Drugs, S. R. Bym, R. R. Pfeiffer, and J. G. Stowell, 2^(nd) Edition,SSCI, West Lafayette, Ind. (1999).

For crystallization techniques that employ solvent, the choice ofsolvent or solvents is typically dependent upon one or more factors,such as solubility of the compound, crystallization technique, and vaporpressure of the solvent. Combinations of solvents may be employed, forexample, the compound may be solubilized into a first solvent to afforda solution, followed by the addition of an antisolvent to decrease thesolubility of the compound in the solution and to afford the formationof crystals. An antisolvent is a solvent in which the compound has lowsolubility.

In one method to prepare crystals, a compound is suspended and/orstirred in a suitable solvent to afford a slurry, which may be heated topromote dissolution. The term “slurry”, as used herein, means asaturated solution of the compound, which may also contain an additionalamount of the compound to afford a heterogeneous mixture of the compoundand a solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization. Seeding may be employed to control growth of aparticular polymorph or to control the particle size distribution of thecrystalline product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in “ProgrammedCooling of Batch Crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 369-377. In general, seeds of small sizeare needed to control effectively the growth of crystals in the batch.Seed of small size may be generated by sieving, milling, or micronizingof large crystals, or by micro-crystallization of solutions. Care shouldbe taken that milling or micronizing of crystals does not result in anychange in crystallinity form the desired crystal form (i.e., change toamorphous or to another polymorph).

A cooled crystallization mixture may be filtered under vacuum, and theisolated solids may be washed with a suitable solvent, such as coldrecrystallization solvent, and dried under a nitrogen purge to affordthe desired crystalline form. The isolated solids may be analyzed by asuitable spectroscopic or analytical technique, such as solid-statenuclear magnetic resonance, differential scanning calorimetry, powderx-ray diffraction, or the like, to assure formation of the preferredcrystalline form of the product. The resulting crystalline form istypically produced in an amount of greater than about 70 weight %isolated yield, preferably greater than 90 weight % isolated yield,based on the weight of the compound originally employed in thecrystallization procedure. The product may be comilled or passed througha mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium ofthe final process for preparing Compound (I). This may be achieved, forexample, by employing in the final process step a solvent or a mixtureof solvents from which Compound (I) may be crystallized. Alternatively,crystalline forms may be obtained by distillation or solvent additiontechniques. Suitable solvents for this purpose include, for example, theaforementioned nonpolar solvents and polar solvents, including proticpolar solvents such as alcohols, and aprotic polar solvents such asketones.

The presence of more than one polymorph in a sample may be determined bytechniques such as powder x-ray diffraction (PXRD) or solid-statenuclear magnetic resonance spectroscopy. For example, the presence ofextra peaks in the comparison of an experimentally measured PXRD patternwith a simulated PXRD pattern may indicate more than one polymorph inthe sample. The simulated PXRD may be calculated from single crystalx-ray data. see Smith, D. K., “A FORTRAN Program for Calculating X-RayPowder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore,Calif., UCRL-7196 (April 1963).

Form A of Compound (I) may be characterized using various techniques,the operation of which are well known to those of ordinary skill in theart. The forms may be characterized and distinguished using singlecrystal x-ray diffraction, which is based on unit cell measurements of asingle crystal at a fixed analytical temperature. A detailed descriptionof unit cells is provided in Stout & Jensen, X-Ray StructureDetermination: A Practical Guide, Macmillan Co., New York (1968),Chapter 3, which is herein incorporated by reference. Alternatively,another means of characterizing the crystalline structure is by powderx-ray diffraction analysis in which the diffraction profile is comparedto a simulated profile representing pure powder material, both run atthe same analytical temperature, and measurements for the subject formcharacterized as a series of 2θ values (usually four or more).

Other means of characterizing the form may be used, such as solid-statenuclear magnetic resonance (ssNMR), differential scanning calorimetry,thermal analysis, and vibrational spectroscopy. These parameters mayalso be used in combination to characterize the subject form.

Utility

Crystalline Form A of Compound (I) can be used to isolate Compound (I)from other components at the completion of the synthesis process; and/orto purify Compound (I) by one or a series of crystallization steps. Theisolation and the purification steps can be combined or practiced asseparate process steps.

EXAMPLE

The invention will now be further described by the following workingexample(s), which are preferred embodiments of the invention. Alltemperatures are in degrees Celsius (° C.) unless otherwise indicated.These examples are illustrative rather than limiting and it is to beunderstood that there may be other embodiments that fall within thespirit and scope of the invention as defined by the claims appendedhereto.

For ease of reference, the following abbreviations may be used herein.

Abbreviations

ACN or MeCN acetonitrile AcOH acetic acid AP area percent aq. aqueousconc. concentrated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCMdichloromethane DIPEA N,N-diisopropylethylamine (Hunig's base) EDC HCl1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride equiv. molarequivalents Et ethyl EtOAc ethyl acetate h hour(s) HOBt 1-hydroxybenzotriazole HPLC high pressure liquid chromatography IPA isopropylalcohol min minute(s) Me methyl NaOH sodium hydroxide MTBE methyltert-butyl ether NMP n-methylpyrrolidone NMR nuclear magnetic resonancePd₂(dba)₃ tris-(dibenzylideneacetone)dipalladium Pd/C palladium oncarbon rt/RT room temperature sat. saturated t-BuOK potassiumtert-butoxide THF tetrahydrofuran TsCl p-toluenesulfonyl chlorideXANTPHOS 4,5-bis(diphenylphosphino)-9,9 dimethylxanthene

Example 1: Preparation of Crystalline Form A of Compound (I)

6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide(1.2 g) was dissolved in 40 mL of dioxane via Rotovap and sonication.After a purge with nitrogen gas for 5 min, 0.6 g ofcyclopropanecarboxamide, 0.3 g of Pd₂(dba)₃, 0.3 g of XANTPHOS, and 2.1g of Cs₂CO₃ were added while still purging. The reaction mixture washeated to 130° C., then filtered and concentrated to remove dioxane.Methanol and DCM were added to dissolve the product after which Celitewas added. The material was dried and purified with ISCO eluting withpure ethyl acetate and the resulting product came off the column toafford Compound (I) as crystalline Form A (100% purity).

Example 2: Preparation of Crystalline Form A of Compound (I)

A solution was prepared by mixing 2 g Compound (I) into 143 mL THF and 7mL water at room temperature (25° C.) until Compound (I) was fullysolubilized. The solution was polish filtered at room temperature andthen dried overnight using a Speedvac. The resulting solid was suspendedin 12 mL of EtOAc at 60° C. and the resulting slurry was aged at 60° C.overnight. The slurry was filtered and the wet cake was washed with 5 mLof EtOAc. The wet cake was dried in a vacuum oven at a temperature inthe range of 50-60° C. to afford 1.5 g of Compound (I) in Form A (98.3%purity).

Example 3: Preparation of Crystalline Form a of Compound (I)

A solution was prepared by charging 1.9 g 1-methylimidazole, 17 mL ACN,3.3 g (²H₃)methanamine, 17.0 g6-cyclopropaneamido-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyridazine-3-carboxylicacid, hemi zinc salt, 17 mL ACN, and 8.5 mL NMP into 34 mL NMP. Thesolution was heated to 65° C. After aging 1 hour at 65° C., 3.3 g HOBtand 10.3 g EDC HCl were charged to the solution to begin the reaction.The solution was aged for 15 minutes to allow for reaction completion,and then 17 mL of ACN was charged. The newly formed slurry was aged at65° C. for 30 minutes after which 17 mL of water and 51 mL of ACN wascharged. The slurry was cooled to −10° C. over 2 hours then aged for 12hours. The cold slurry was filtered and the crystalline solids werewashed with 51 mL of 2:1 water:ACN followed by 51 mL of ACN. The wetcake was dried in a vacuum oven at a temperature in the range of 50-100°C. to afford Compound (I) in Form A.

Example 4: Preparation of Crystalline Form A of Compound (I)

A solution was prepared by mixing 10 g Compound (I) into 55 mL NMP andheating the slurry to 70° C. until Compound (I) was fully solubilized.The solution was polish filtered with the temperature of the batch inthe range of 62.5-85° C. The filtrate was warmed up to 70° C. and then30 mL of IPA was added to the batch. The batch was allowed to return to70° C., at which point 1 wt % of Compound (I) seeds were added. Thenewly formed slurry was aged for 1 hour at 70° C. after which 60 mL ofIPA was charged to the batch over one hour. The slurry was cooled to−10° C. over 3.5 hours. The cold slurry was aged at −10° C. for 12hours. The cold slurry was filtered and the crystalline solids werewashed 2×40 mL IPA. The wet cake was dried in a vacuum oven at atemperature in the range of 50-100° C. to afford 8.5 g of Compound (I)in Form A (>99.9 AP purity).

Synthesis of6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide Step 1: Preparation ofCompound 2

To a glass lined reactor were charged toluene (0.26 kg), sulfolane (3.4kg), Compound 1 (1.0 kg) and POCl₃ (2.7 kg). The crude was cooled to 0°C. Triethylamine (0.89 kg) was charged, and the resulting crude mixturewas heated to 65° C. and aged till the reaction reached completion. Thereaction mass was cooled to 5° C.

In a separate reactor, water (7.5 kg) was charged and cooled to 5° C.The reaction mass was added slowly to the water solution, maintainingthe internal temperature below 5° C. Additional water (0.5 kg) was usedto rinse the reactor and aid the transfer. The resulting mixture wasagitated at 5° C. for 3 hours, then extracted with MTBE three times(3×4.5 kg). The combined organic layers were washed sequentially withaqueous pH 7 buffer solution (5.0 L/kg, 15 wt % KH₂PO₄/K₂HPO₄) and water(2.5 kg). The crude was distilled under vacuum until total volume becameapproximately 3 L/kg. ACN (2×6.3 kg) was added followed by additionaldistillations back to −3 L/kg. The crude was cooled to 20° C. to affordCompound 2 as a 30-36 wt % solution in 90-95% yield.

Step 2: Preparation of Compound 3

ACN (2.7 kg), lithium bromide (1.18 kg) and water (0.65 kg) were chargedto a glass-lined reactor at 25° C. Compound 2 crude solution preparedabove (limiting reagent) was added, followed by DIPEA (1.82 kg). Theresulting slurry was agitated at 25° C. until the reaction reachedcompletion. The product was isolated by filtration. The crude solid waswashed with ACN (1.6 kg). The cake was dried under vacuum at 45° C.Compound 3 was isolated in 98 AP and 83% yield.

Step 3: Preparation of Compound 8

Water (6.0 kg, 6.0 L/kg) and Compound 7 (1.0 kg) were charged to aglass-lined reactor at 25° C. Zinc acetate dehydrate (1.08 kg, 1.0equiv) was added, followed by Compound 3 (1.28 kg, 1.20 equiv). Thereactor line was rinsed with 2-propanol (0.79 kg, 1.0 L/kg) and water(1.50 kg, 1.50 L/kg). The resulting homogeneous solution was heated to65° C. and aged until the reaction reached completion. Water (7.0 kg,7.0 L/kg) was added, and the crude mixture was cooled to 20° C. and agedfor 30 min. The product was isolated by filtration. The crude solid waswashed sequentially with water (6.0 kg, 6.0 L/kg), water (6.0 kg, 6.0L/kg), THF (5.3 kg, 6.0 L/kg) and THF (5.3 kg, 6.0 L/kg). The cake wasdried under vacuum at 70° C. Compound 8 was isolated in 98 AP and 94%yield.

Step 4: Preparation of Compound 9

A separate glass-lined reactor was flushed with nitrogen. Toluene (0.87kg, 1.0 L/kg) and MeCN (0.79 kg, 1.0 L/kg) were charged, followed by(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl) phosphino]ethyl]-2-(dicyclohenxyphosphino)ferrocene (Josiphos SL-009-01) (14.1 g,1.0 mol %) and palladium acetate (2.9 g, 0.5 mol %). The reactor linewas rinsed with toluene (0.43 kg, 0.5 L/kg). The resulting pre-formedcatalyst solution was kept under nitrogen until further usage.

At 20° C., toluene (3.46 Kg, 4.0 L/kg) and ACN (1.57 kg, 2.0 L/kg) werecharged to a glass-lined reactor flushed with nitrogen. Compound 8 (1.00kg) was added, followed by DBU (0.39 kg, 1.00 equiv). The reactor linewas rinsed with toluene (0.43 kg, 0.5 L/kg). Compound 10 (0.54 kg, 2.5equiv) and K₂CO₃ (325 mesh grade, 0.70 kg, 2.0 equiv) were added to thereaction mixture, followed by toluene (1.30 kg, 1.5 L/kg) and ACN (0.79kg, 1.0 L/kg). The pre-formed catalyst solution was transferred into thereaction mixture, which was then heated to 75° C. and agitated until thereaction reached completion.

The reaction crude was cooled to 20° C. Aqueous acetic acid (50 Volume%, 4.0 kg, 4.0 L/kg) was charged slowly over the course of 1 h. Glacialacetic acid (10.5 kg, 10.0 L/kg) was then added. The resultinghomogeneous solution was washed twice with heptane (2×3.42 kg, 2×5.0L/kg). The bottom aqueous layer was collected and transferred to a cleanreactor. Water (5.0 kg, 5.0 L/kg) was added, followed by Compound 9seeds (0.01 kg, 1.0 wt %). The slurry was aged for 2 h at 20° C.Additional water (2.0 kg, 2.0 L/kg) was added, and the slurry wasfurther aged for 6 h. The product was isolated by filtration. The crudecake was washed with aqueous ACN (50 Volume %, 4.5 kg, 5.0 L/kg)followed by ACN (3.9 kg, 5.0 L/kg). The cake was dried under vacuum at65° C. Compound 9 was isolated in 98.5 AP and 84% yield.

Step 5: Preparation of the Compound (I)

NMP (2.06 kg, 2.0 L/kg) and ACN (0.78 kg, 1.0 L/kg) were charged to aglass-lined reactor and agitated at 20° C. N-Methylimidazole (0.13 kg,0.7 equiv.), Compound 13 (0.17 kg, 1.2 equiv.) and Compound 9 (1.00 kg)were charged to the reaction mixture. The mixture was heated to 65° C.and aged until homogeneous. HOBt 20% wet (0.17 kg, 0.5 eq), followed byEDC HCl (0.54 kg, 1.4 eq) were then charged to the reaction mixture. Thereactor was rinsed with ACN (0.78 kg, 1.0 L/kg), then the resultingmixture was aged at 65° C. until the reaction reached completion. Thereaction was quenched by charging water (1.0 kg, 1 L/kg), then dilutedwith ACN (3.0 kg, 3 L/kg). The reaction mixture was aged at 65° C. for 1h, before cooling to 0° C., and aged for an additional 12 h at 0° C. Theproduct was isolated by filtration. The wet cake was washed with 2:1Water:ACN (2.8 kg, 3 L/kg) then ACN (2.4 kg, 3 L/kg), before dryingunder full vacuum at 65° C. Compound I was isolated in >99.5% purity and91% yield.

NMP (6.2 kg, 6.0 L/kg) and Compound I (1.0 kg) were charged to aglass-lined reactor. The batch was heated to 70° C. to form a paleyellow solution, which was then transferred through a polish filter to aclean vessel at 70° C. 2-Propanol (2.4 kg, 3 L/kg) was added, followedby Compound I seeds (0.005 kg, 0.005 kg/kg). After aging for 1 h,additional 2-propanol (4.8 kg, 6 L/kg) was charged over the course of 2h (3 L/kg/hr). The slurry was aged for 1 h at 70° C., cooled slowly to0° C. and aged for additional 12 h at 0° C. Product was isolated byfiltration. The wet cake was washed with 2-propanol (2×3.1 kg, 2×4 L/kg)before drying under full vacuum at 65° C. Compound I was isolatedin >99.9% purity and 83% yield.

Preparation of Compound 7 Step 1: Preparation of N-methyl-N-formylhydrazine

To a glass lined reactor were charged methanol (1.6 kg/kg, 2.0 L/kg) andmethyl hydrazine (1 kg) at 0° C. Methyl formate (0.57 kg/kg, 1.1 equiv)was added drop-wise. The crude was warmed up to 20° C. and aged foradditional 6 h. The crude was distilled under vacuum until total volumebecame approximately 0.5 L/kg. Five put/take distillations with 2-MeTHF(5×3.6 kg/kg) were undertaken for the purpose of azeotropic drying. Thecrude was cooled to 20° C. N-Methyl-N-formyl hydrazine was isolated as89-90 wt % solution in 89-91% yield.

Step 2: Preparation of Compound 5

To a glass lined reactor were charged potassium tert-butoxide (1.5kg/kg, 2.4 equiv) and THF (12.2 kg/kg) at 0° C. A mixture of Compound 4(1.0 kg), N-methyl-N-formyl hydrazine (1.0 kg/kg, 2.30 equiv) and THF(5.3 kg/kg, 6.0 L/kg) was added slowly. The reactor line was rinsed withTHF (0.5 kg/kg). The reaction crude was aged at 0° C. until reactionreached completion. Water (5.0 kg/kg) was added, and the resultingmixture was aged at 0° C. for 30 min, heated to 40° C. and aged foradditional 30 min. The layers were separated and the aqueous layer wasdiscarded. The organic layer was washed with brine (15 wt %, 5.7 kg/kg)before distilling under vacuum until total volume became approximately 5L/kg. Four put/take distillations with ethyl acetate (4×10 L/kg) wereundertaken for the purpose of azeotropic drying. The crude was cooled to20° C. Sulfuric acid (0.66 kg/kg, 1.10 equiv.) was added, and the slurrywas agitated for 2-3 h. Product was isolated by filtration. The cake wasconsecutively washed with ethyl acetate (2×6.5 L/kg) and heptane (8L/kg), and dried under vacuum at 45° C. Compound 5 was isolated in 99 APand 83% yield.

Step 3: Preparation of Compound 6

To a glass lined reactor were charged concentrated sulfuric acid (4.5kg/kg) and Compound 5 (1.0 kg) at 0-5° C. Nitric acid (68 wt %, 0.35kg/kg, 1.2 equiv) was added drop-wise. The mixture was agitated at 0-5°C. until reaction reached completion.

In a separate reactor, water (12 kg/kg) and methanol (6.5 kg/kg, 8.3L/kg) were mixed well at 20° C. The nitration crude was transferredslowly into the methanol water mixture. The reactor line was rinsed withmethanol (0.5 kg/kg). The crude was heated to 40-45° C. Aqueous ammoniumhydroxide (25 wt %, 7.4 kg/kg) was added slowly. The resulting slurrywas cooled to 20° C. and agitated for 3 h. Product was isolated byfiltration. The cake was washed with water (2×6 L/kg), and dried undervacuum at 45° C. Compound 6 was isolated in 99 AP and 95% yield.

Step 4: Preparation of Compound 7

To a high pressure reactor flushed with nitrogen were charged methanol(8.0 kg/kg) and Compound 6 (1.0 kg). With careful exclusion of oxygen,sodium bicarbonate (0.6 kg/kg, 2.0 equiv.) and Pd/C (10% loading, 50%wet, 0.02 kg/kg) were added. The reactor was pressurized with hydrogen(41-46 psi), and the reaction mixture was aged at 20° C. for 6 h thenheated to 45° C. and aged till reaction reached completion. The reactorwas flushed with nitrogen, and the reaction crude was filtered to removePd/C. Methanol (5 kg/kg) was used to aid the transfer. The combinedfiltrates were distilled under vacuum until total volume becameapproximately 2.5 L/kg. Water (10 kg/kg) was added, and the crude wasdistilled under vacuum until total volume became approximately 2.5 L/kg.The crude was heated to 70° C. Brine (25 wt %, 9.0 kg/kg) was added, andthe resulting crude was agitated for 6 h at 70° C. After cooling down to0° C., the crude was further aged for 6 h. Product was isolated byfiltration. The cake was washed with brine (pre-cooled to 0° C., 25 wt%, 2.0 kg/kg), and dried under vacuum at 45° C. Compound 7 was isolatedin 99 AP and 88% yield.

Preparation of Compound 13 Step 1: Preparation of Compound 11 andCompound 12

To a glass lined reactor flushed with nitrogen were charged water (16.3L/kg) and sodium hydroxide (3.3 kg, 3.0 equiv). The mixture was agedtill sodium hydroxide reached full dissolution. The crude was cooled to0° C. d₄-Methanol (1.0 kg) and THF (4.5 L/kg) were charged. A solutionof TsCl (6.3 kg, 1.2 equiv) in THF (6.3 kg, 7.1 L/kg) was added over thecourse of 2 h. The crude was agitated at 0° C. until reaction reachedcompletion. The batch was warmed to 20° C. The layers were separated.The collected organic layer was diluted with MTBE (4.0 kg, 5.4 L/kg),washed with brine twice (25 wt %, 4.0 kg followed by 12 kg). The organiclayer was distilled under vacuum until total volume became approximately10 L/kg. Two put/take distillations with ACN (2×10 L/kg) were undertakenfor the purpose of azeotropic drying. The crude was cooled to 20° C. ACN(10.0 kg, 12.8 L/kg) and NaN(CHO)₂ (3.3 kg, 1.2 equiv.) were added. Thecrude was heated to 65° C. and agitated until reaction reachedcompletion. After cooling down to 5° C., the mixture was filtered, andthe crude cake was washed with ACN twice (2×2.5 kg, 2×3.2 L/kg). Thecombined filtrates were distilled under vacuum until total volume becameapproximately 3 L/kg. The crude was cooled to 20° C. Compound 12 wasisolated as an oil with 80-85 wt % in 60-70% yield.

Step 2: Preparation of Example 13

To a glass lined reactor were charged Compound 12 (1.0 kg) and methanol(3.9 kg, 5.0 L/kg) at 20° C. A solution of HCl in IPA (5-6 Normal, 4.5kg, 1.5 equiv) was added. The resulting mixture was heated to 50° C. andagitated until reaction reached completion. THF (10 kg, 11.2 L/kg) wasadded slowly and the crude was cooled to 0° C. over 2 h to afford aslurry. The product was isolated by filtration. The cake was washed withTHF (3.7 kg, 4.1 L/kg), and dried under vacuum at 45° C. Compound 13 wasisolated in 80% yield.

Optional Recrystallization of Compound 13:

Methanol (5.6 kg, 8.3 L/kg) and Compound 13 (1.0 kg) were charged to aglass-lined reactor. DBU (0.1 kg) was added slowly. The crude wasagitated for 1 h. THF (12.4 kg, 13.9 L/kg) was added slowly, and theresulting slurry was aged for 2 h. The product was isolated byfiltration. The cake was washed with THF (2.6 kg, 2.9 L/kg), and driedunder vacuum at 45° C. Compound 13 was isolated in 60% yield (1^(st)crop). The mother liquor was distilled under vacuum until total volumebecame approximately 1 L/kg. Two put/take distillations with methanol(2×2.8 kg, 2×3.6 L/kg) were performed and the solution was concentratedback to ˜1 L/kg. The crude was cooled to 20° C. THF (4.8 kg, 5.4 L/kg)was added, and the resulting slurry was aged for 2 h. The product wasisolated by filtration. The cake was washed with THF (1.0 kg), and driedunder vacuum at 45° C. Compound 13 was isolated in 25% yield (2nd crop).

Example 5: Physical and Chemical Stability of Form a of Compound (I)

Samples of micronized Form A of Compound (I) were stored at differentconditions of temperature and humidity for 4 weeks. The physicalstability, characterized by DSC, TGA, and PXRD, were measured at 2 and 4weeks. No change in the physical form was detected in the samples storedfor 4 weeks. The data in Table 2 show that there were no measure changein chemical stability of the samples.

TABLE 2 % Assay Storage Conditions 2 weeks 4 weeks 5° C. (control) 99.299.2 25° C./60% relative 99.2 99.2 humidity (closed) 40° C./75% relative99.2 99.2 humidity (open) 50° C. 99.2 99.2 High Intensity 99.3 99.2Light/UV

The moisture sorption isotherm of Form A of Compound (I) is shown inFIG. 4. Form A of Compound (I) is non-hygroscopic with less than 0.1weight % gain between 25 to 75% relative humidity at 25° C.

The results showed that Form A of Compound (I) is a non-hygroscopicmaterial, retained good potency, had no significant physical or chemicaldegradation, and its impurity profiles remain unchanged at the testedtemperature and humidity conditions.

Single Crystal Data

Single crystal X-ray data was collected using a Bruker Kappadiffractometer equipped with an APEX II CCD detector and a MICROSTARmicrofocus rotating anode X-ray generator of monochromatic Cu Kαradiation (λ=1.54178 Å). The single crystal was at room temperature(approximately 25° C.) during data collection.

The final unit cell parameters were determined using the full data set.The structures were solved by direct methods and refined by full-matrixleast-squares approach using the SHELXTL software package (G. M.Sheldrick, SHELXTL, Bruker AXS, Madison, Wis. USA.). Structurerefinements involved minimization of the function defined byΣw(|F₀|−|F_(c))², where w is an appropriate weighting factor based onerrors in the observed intensities, F_(o) is the structure factor basedon measured reflections, and F_(c) is the structure factor based oncalculated reflections. Agreement between the refined crystal structuremodel and the experimental X-ray diffraction data is assessed by usingthe residual factors R=Σ∥F_(o)|−|F_(c)∥/Σ|F_(o) andwR=[Σw(|F_(o)|−|F_(c))²/Σw|F_(o)|]^(1/2). Difference Fourier maps wereexamined at all stages of refinement. All non-hydrogen atoms wererefined with anisotropic thermal displacement parameters. Hydrogen atomswere generally calculated using idealized geometry, assigned isotropictemperature factors, and included in structure factor calculations withfixed parameters.

PXRD

X-ray powder diffraction (PXRD) data were obtained using a Bruker C2GADDS with Vantec-500 detector. The radiation was Cu Kα (40 KV, 40 mA).The sample-detector distance was ˜20 cm. Incident optics include Goebelmirror and 0.3 mm collimator. Powder samples were placed in sealed glasscapillaries of 1 mm or less in diameter; the capillary was rotatedduring data collection. Data were collected for 2≤2θ≤35° with a sampleexposure time of at least 1000 seconds. The resulting two-dimensionaldiffraction arcs were integrated to create a traditional 1-dimensionalPXRD pattern with a step size of 0.05 degrees 2θ in the range of ˜2 to˜30 degrees 2θ.

DSC

Differential scanning calorimetry (DSC) experiments were performed in aTA Instruments™ model Q2000. The sample (about 2-6 mg) was weighed in analuminum pan and recorded accurately recorded to a hundredth of amilligram, and transferred to the DSC. The instrument was purged withnitrogen gas at 50 mL/min. Data were collected between room temperatureand 300° C. at 10° C./min heating rate. The plot was made with theendothermic peaks pointing down.

TGA (Open Pan)

Thermal gravimetric analysis (TGA) experiments were performed in a TAInstruments™ model Q5000. The sample (about 10-30 mg) was placed in aplatinum pan previously tared. The weight of the sample was measuredaccurately and recorded to a thousand of a milligram by the instrument.The furnace was purged with nitrogen gas at 100 mL/min. Data werecollected between room temperature and 300° C. at 10° C./min heatingrate.

VTI

Moisture-sorption isotherms were collected in a TA Instrument VTI-SA+Vapor Sorption Analyzer using approximately 10 mg of sample. The samplewas dried at 60° C. until the loss rate of 0.0005 wt %/min was obtainedfor 10 minutes. The sample was tested at 25° C. and 3 or 4, 5, 15, 25,35, 45, 50, 65, 75, 85, and 95% relative humidity (RH). Equilibration ateach relative humidity was reached when the rate of 0.0003 wt %/min for35 minutes was achieved or a maximum of 600 minutes.

What is claimed is:
 1. Crystalline Form A of6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide.
 2. The crystalline formaccording to claim 1 characterized by at least one of the following: (i)a unit cell parameters substantially equal to the following:a=8.90±0.05 Åb=10.48±0.05 Åc=11.34±0.05 Åα=96.7±0.5°β=90.8±0.5°γ=100.4±0.5° Space group: P-1 Molecules per unit cell (Z): 2 wherein theunit cell parameters of Form A of Compound (I) are measured at atemperature of about 25° C.; (ii) a powder x-ray diffraction patterncomprising four or more 2θ values (CuKα λ=1.5418 Å) selected from:7.8±0.2; 8.7±0.2; 10.1±0.2; 12.0±0.2; 12.4±0.2; 13.0±0.2; 15.8±0.2;18.9±0.2; 19.3±0.2; and 20.4±0.2, wherein the PXRD pattern of Form A ismeasured at a temperature of about 25° C.; (iii) an observed powderx-ray diffraction pattern substantially as shown in FIG. 1; or (iv) anendotherm in the range of from 264° C. to 269° C.
 3. The crystallineform according to claim 1 characterized by a powder x-ray diffractionpattern comprising five or more 20 values (CuKα λ=1.5418 Å) selectedfrom: 7.8±0.2; 8.7±0.2; 10.1±0.2; 12.0±0.2; 12.4±0.2; 13.0±0.2;15.8±0.2; 18.9±0.2; 19.3±0.2; and 20.4±0.2, wherein the PXRD pattern ofForm A is measured at a temperature of about 25° C.
 4. The crystallineform according to claim 1 characterized by a powder x-ray diffractionpattern comprising 2θ values (CuKα X=1.5418 Å) at 10.1±0.2 and 15.8±0.2;and three or more 2θ values (CuKα λ=1.5418 Å) selected from: 7.8±0.2;8.7±0.2; 12.0±0.2; 12.4±0.2; 13.0±0.2; 15.8±0.2; 18.9±0.2; and 19.3±0.2,wherein the PXRD pattern of Form A is measured at a temperature of about25° C.
 5. The crystalline form according to claim 1 characterized by (i)a powder x-ray diffraction pattern comprising the 2θ values (CuKαλ=1.5418 Å) at 10.1±0.2 and 15.8±0.2, measured at a temperature of about25° C.; and (ii) an endotherm in the range of from 264° C. to 269° C. 6.The crystalline form according to claim 1 characterized by (i) a powderx-ray diffraction pattern comprising the 20 values (CuKα λ=1.5418 Å) at10.1±0.2 and 15.8±0.2, measured at a temperature of about 25° C.; and(ii) a differential scanning calorimetry (DSC) thermogram substantiallyas shown in FIG.
 2. 7. The crystalline form according to claim 1consisting essentially of Form A.
 8. The crystalline form according toclaim 1 wherein said Form A is in substantially pure form.
 9. Acomposition comprising6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide, wherein at least 95 wt. %of said6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide is in crystalline Form A.